# The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $719,259

## Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant
and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical
cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of
graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the
transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this
damaging T cell reactivity. We previously demonstrated in a preclinical mouse model of allo-HSCT that the
autophagy protein ATG16L1 is essential for preventing intestinal inflammation and GVHD. Autophagy is a
process by which cytosolic material is delivered to the lysosome for degradation, and is involved in maintaining
cellular and tissue homeostasis. Additionally, a common polymorphism in ATG16L1 leading to a coding
change (T300A) is associated with susceptibility to inflammatory bowel disease (IBD) and transplant-related
mortality in allo-HSCT patients. Given the high prevalence of the T300A variant and the challenges associated
with treating intestinal GVHD, addressing the mechanism by which ATG16L1 and autophagy protect against
intestinal damage is a research priority.
 During the previous funding period, we made significant progress by demonstrating that ATG16L1
prevents necroptosis in intestinal epithelial cells (IECs) following allo-HSCT. Necroptosis is a form of
programmed necrosis that has received attention as a therapeutic target for limiting the tissue damage
observed in a range of inflammatory diseases. Our findings suggest that the intersection between autophagy
and necroptosis can be targeted to treat GVHD, especially in high risk patients such as individuals harboring
the ATG16L1T300A variant. However, the molecular basis for the interaction between ATG16L1 and necroptosis
is obscure, and the upstream signals that trigger the adverse signaling events require examination. Thus, we
lack detailed mechanistic understanding of the inflammatory process that is necessary to apply such strategies
to allo-HSCT recipients. The goal of this proposal is to how ATG16L1 and autophagy integrate IEC-intrinsic
and -extrinsic signals to block necroptosis following allo-HSCT, and determine how the T300A variant disrupts
this protective function. We anticipate this knowledge will yield significant insight into GVHD pathogenesis and
inform intervention strategies for improving allo-HSCT outcome.

## Key facts

- **NIH application ID:** 9915940
- **Project number:** 5R01HL123340-06
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Ken Hashigiwa Cadwell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,259
- **Award type:** 5
- **Project period:** 2015-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915940

## Citation

> US National Institutes of Health, RePORTER application 9915940, The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1 (5R01HL123340-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9915940. Licensed CC0.

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